tbuckley/cabot-search huggingface dataset:
Facts and Hopes for Immunotherapy in Renal Cell Carcinoma
Authors: Chen Yao, Tian Zhang, Tuoqi Wu, James Brugarolas
Journal: Clinical Cancer Research (2022)

Abstract Immunotherapy has made a significant impact in many tumors, including renal cell carcinoma (RCC). RCC has been known to be immunoresponsive since the cytokine era of IFNα and IL2, but only a small number of patients had durable clinical benefit. Since then, discoveries of key tumor drivers, as well as an understanding of the contribution of angiogenesis and the tumor microenvironment (TME), has led to advances in drug development, ultimately transforming patient outcomes. Combinations of anti-angiogenic agents with immune checkpoint inhibitors are now standard of care. Current challenges include patient selection for immunotherapy combinations, resistance acquisition, and optimally sequencing therapies. Further discoveries about RCC biology, the TME, and resistance mechanisms will likely pave the way for the next generation of therapies.
Sublingual Dexmedetomidine vs Placebo and Acute Agitation Associated With Bipolar Disorder
Authors: Akiko Abe, Yuma Takeda, Hiroto Ishiki
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Reply
Authors: Georg Schett, David Simon, Filippo Fagni, Korey Tascilar
Journal: Arthritis & Rheumatology (2022)

We thank Dr. Niu and colleagues for their remark that prolonged glucocorticoid treatment increases the susceptibility to COVID-19 acquisition and decreases the response to vaccination (1). In relation to our study, the authors asked about the potential effects of concomitant glucocorticoid therapy on blunted vaccination responses in rituximab-treated patients with AID. It has been known since the 1970s that glucocorticoids reduce T cell (2, 3) and B cell (4, 5) activation and thereby inhibit mounting of adaptive immune responses against infections. When interrogating whether background glucocorticoid treatment could have added to the reduced immune responses to vaccination or infection with SARS–CoV-2, we found no major exposure to glucocorticoid treatment in this cohort. Only 3 patients (1 vaccinated and 2 infected with SARS–CoV-2) were receiving glucocorticoids. Furthermore, doses of glucocorticoids were low (mean ± SD 4.6 ± 3.8 mg prednisolone/day). Hence, it is unlikely that the background glucocorticoids were responsible for the impaired immune response in the vaccinated patients or the patients with SARS–CoV-2 infection. Another potential source of glucocorticoids in this context is their administration in combination with rituximab infusion, in which patients receive a single shot of 25 mg of prednisolone together with rituximab infusion. Previous data from patients with shock (6) and those experiencing asthma episodes (7, 8), in whom systemic bolus glucocorticoids are also frequently used for short-term treatment, have not shown that such treatment affected the responses to tetanus (6) or influenza vaccines (7, 8). Short-term glucocorticoid treatment also did not seem to affect the immune response to the SARS–CoV-2 vaccine (9). Therefore, we cannot assume that the single dose of glucocorticoids significantly contributed to the observed blunted humoral immune responses to SARS–CoV-2 in rituximab-treated patients. The observation that T cell responses are maintained, while B cell responses are severely suppressed, in rituximab-treated patients with AIDs supports a specific effect of B cell–depleting agents rather than of glucocorticoids that would also impair T cell activation. These findings and the comments raised by Niu and colleagues, however, also suggest that continuous higher doses of glucocorticoids may be problematic in B cell–depleted patients, as immune responses to infection and vaccinations largely depend on intact T cell responses if B cells are absent. Open access funding enabled and organized by Project DEAL.
Clinical Protection During the First Omicron Wave in Unvaccinated, Convalescent US Adults
Authors: Mars Stone, Eduard Grebe, Michael P. Busch
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
My Body Recalls a Day
Authors: Sydney Lea
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Pharmacologic Targeting of TFIIH Suppresses KRAS-Mutant Pancreatic Ductal Adenocarcinoma and Synergizes with TRAIL
Authors: Russell Moser, James Annis, Olga Nikolova, Cliff Whatcott, Kay Gurley, Eduardo Mendez, Kim Moran-Jones, Craig Dorrell, Rosalie C. Sears, Calvin Kuo, Haiyong Han, Andrew Biankin, Carla Grandori, Daniel D. Von Hoff, Christopher J. Kemp
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) typically presents as metastatic disease at diagnosis and remains refractory to treatment. Next-generation sequencing efforts have described the genomic landscape, classified molecular subtypes, and confirmed frequent alterations in major driver genes, with coexistent alterations in KRAS and TP53 correlating with the highest metastatic burden and poorest outcomes. However, translating this information to guide therapy remains a challenge. By integrating genomic analysis with an arrayed RNAi druggable genome screen and drug profiling of a KRAS/TP53 mutant PDAC cell line derived from a patient-derived xenograft (PDCL), we identified numerous targetable vulnerabilities that reveal both known and novel functional aspects of pancreatic cancer biology. A dependence on the general transcription and DNA repair factor TFIIH complex, particularly the XPB subunit and the CAK complex (CDK7/CyclinH/MAT1), was identified and further validated utilizing a panel of genomically subtyped KRAS mutant PDCLs. TFIIH function was inhibited with a covalent inhibitor of CDK7/12/13 (THZ1), a CDK7/CDK9 kinase inhibitor (SNS-032), and a covalent inhibitor of XPB (triptolide), which led to disruption of the protein stability of the RNA polymerase II subunit RPB1. Loss of RPB1 following TFIIH inhibition led to downregulation of key transcriptional effectors of KRAS-mutant signaling and negative regulators of apoptosis, including MCL1, XIAP, and CFLAR, initiating caspase-8 dependent apoptosis. All three drugs exhibited synergy in combination with a multivalent TRAIL, effectively reinforcing mitochondrial-mediated apoptosis. These findings present a novel combination therapy, with direct translational implications for current clinical trials on metastatic pancreatic cancer patients. Significance: This study utilizes functional genetic and pharmacological profiling of KRAS-mutant pancreatic adenocarcinoma to identify therapeutic strategies and finds that TFIIH inhibition synergizes with TRAIL to induce apoptosis in KRAS-driven pancreatic cancer.
Genome-Wide Association Study of Obstructive Sleep Apnea and Objective Sleep-related Traits Identifies Novel Risk Loci in Han Chinese Individuals
Authors: Huajun Xu, Feng Liu, Zhiqiang Li, Xinyi Li, Yuenan Liu, Niannian Li, Xiaoxu Zhang, Zhenfei Gao, Xiaoman Zhang, Yupu Liu, Jianyin Zou, Lili Meng, Suru Liu, Huaming Zhu, Xulan Tang, Hongmin Wu, Kaiming Su, Bin Chen, Dongzhen Yu, Haibo Ye, Haoyan Chen, Hongliang Yi, Shankai Yin, Jian Guan, Yongyong Shi
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Previous genetic studies of obstructive sleep apnea (OSA) have limitations in terms of precise case definition, integrated quantitative traits, and interpretation of genetic functions; thus, the heritability of OSA remains poorly explained. Objectives: To identify novel genetic variants associated with OSA and objective sleep-related traits and to explore their functional roles. Methods: A genome-wide association study was performed in 20,590 Han Chinese individuals (5,438 OSA and 15,152 control samples). Human samples and point mutation knockin mice were used for follow-up investigation of gene functions. Measurements and Main Results: Two characteristic study-wide significant loci (P < 2.63 × 10-9) for OSA were identified: the PACRG intronic variant rs6455893 on 6q26 (odds ratio [OR] = 1.62; 95% confidence interval [CI], 1.39-1.89; P = 6.98 × 10-10) and the missense variant rs3746804 (p.Pro267Leu) in the riboflavin transporter SLC52A3 on 20p13 (OR = 0.83; 95% CI, 0.79-0.88; P = 7.57 × 10-10). In addition, 18 genome-wide significant loci associated with quantitative OSA and objective sleep-related traits were identified, 5 of which exceeded the study-wide significance threshold. Rs3746804 was associated with elevated serum riboflavin concentrations, and the corresponding mutation in mice increased riboflavin concentrations, suggesting that this variant may facilitate riboflavin uptake and riboflavin-dependent physiological activity. Conclusions: We identified several novel genome-wide significant loci associated with OSA and objective sleep-related traits. Our findings provide insight into the genetic architecture of OSA and suggest that SLC52A3 might be a therapeutic target, whereas riboflavin might be a therapeutic agent.
Intratumoral Heterogeneity and Immune Modulation in Lung Adenocarcinoma in Female Smokers and Never Smokers
Authors: Timo B. Trefzer, Marc A. Schneider, Katharina Jechow, Robert Lorenz Chua, Thomas Muley, Hauke Winter, Mark Kriegsmann, Michael Meister, Roland Eils, Christian Conrad
Journal: Cancer Research (2022)

Single-cell analysis of healthy lung tissue and lung cancer reveals distinct tumor cell populations, including cells with differential immune modulating capacity between smokers and never smokers, which could guide future therapeutic strategies.
Dual Anti-HIV Antibodies Provide Long-term Viral Suppression
Authors: Howard D. Larkin
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Association of Metabolic Syndrome With Incident Dementia: Role of Number and Age at Measurement of Components in a 28-Year Follow-up of the Whitehall II Cohort Study
Authors: Marcos D. Machado-Fragua, Aurore Fayosse, Manasa Shanta Yerramalla, Thomas T. van Sloten, Adam G. Tabak, Mika Kivimaki, Séverine Sabia, Archana Singh-Manoux
Journal: Diabetes Care (2022)

OBJECTIVE Previous research suggests an inconsistent association between Metabolic syndrome (MetS) and incident dementia. We examined the role of number of MetS components and age at their assessment for incident dementia. RESEARCH DESIGN AND METHODS MetS components (fasting glucose, triglycerides, waist circumference, blood pressure, and HDL cholesterol) on 7,265, 6,660, and 3,608 participants at &amp;lt;60, 60 to &amp;lt;70, and ≥70 years of age were used to examine associations with incident dementia using cause-specific Cox regression. RESULTS Analyses of MetS measured at &amp;lt;60, 60 to &amp;lt;70, and ≥70 years involved 393 (5.4%), 497 (7.5%), and 284 (7.9%) dementia cases over a median follow-up of 20.8, 10.4, and 4.2 years, respectively. Every additional MetS component before 60 (hazard ratio [HR] 1.13 [95% CI 1.05, 1.23]) and 60 to &amp;lt;70 (HR 1.08 [95% CI 1.00, 1.16]) but not ≥70 years (HR 1.04 [95% CI 0.96, 1.13]) was associated with higher dementia risk. MetS defined conventionally (≥3 components) before 60 years (HR 1.23 [95% CI 0.96, 1.57]), between 60 and 70 years (HR 1.14 [95% CI 0.91, 1.42]), or &amp;gt;70 years of age (HR 1.10 [95% CI 0.86, 1.40]) was not associated with incident dementia. Multistate models showed higher risk of dementia in those with ≥1 (HR 1.99 [95% CI 1.08, 3.66]) and ≥2 MetS components (HR 1.69 [95% CI 1.12, 2.56]) before 60 years of age, even when they remained free of cardiovascular disease over the follow-up. CONCLUSIONS Risk of incident dementia increases with every additional MetS component present in midlife rather than after accumulation of three components; only part of this risk is mediated by cardiovascular disease.
Sublingual Dexmedetomidine vs Placebo and Acute Agitation Associated With Bipolar Disorder
Authors: Phillip Harrison Henry, Bezalel Dantz
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Assessing the Immune Cell Subset and Genetic Mutations in Patients With Palindromic Rheumatism Seronegative for Rheumatoid Factor and Anti–Cyclic Citrullinated Peptide
Authors: Chin‐An Yang, Ju‐Pi Li, Yi‐Hua Lai, Ya‐Ling Huang, Chien‐Yu Lin, Joung‐Liang Lan
Journal: Arthritis & Rheumatology (2022)

Objective The etiology underlying cases of palindromic rheumatism (PR) not associated with other rheumatic diseases in patients who are seronegative for rheumatoid factor and anti–cyclic citrullinated peptide (seronegative PR) is unclear. We aimed to investigate the immune cells and genes involved. Methods This was a single‐center comparative study of 48 patients with seronegative PR and 48 healthy controls. Mass cytometry and RNA sequencing were used to identify distinct immune cell subsets in blood. Among the 48 seronegative PR patients, plasma samples from 40 patients were evaluated by enzyme‐linked immunosorbent assay for cytokine levels, and peripheral blood samples from 25 patients were evaluated by flow cytometry for mononuclear cell subsets. Plasma samples from 21 patients were evaluated by real‐time polymerase chain reaction for differential gene and protein expression, and samples from 3 patients were analyzed with whole‐exome sequencing for gene mutations. Results Immunophenotyping revealed a markedly increased frequency of CD14+CD11b+CD36+ and CD4+CD25–CD69+ cells in seronegative PR patients with active flares compared with healthy controls ( P &lt; 0.0001 for both cell subset comparisons). Gene enrichment analyses of RNA‐sequencing data from sorted CD14+CD11b+CD36+ and CD4+CD25–CD69+ cells showed involvement of the inflammatory/stress response, phagocytosis, and regulation of apoptosis functional pathways. Up‐regulated expression of CXCL16 and IL10RA was observed in monocytes from PR patients. Up‐regulation of PFKFB3 , DDIT4 , and TGFB1, and down‐regulation of PDIA6 were found in monocytes and lymphocytes from PR patients with active flares and PR patients in intercritical periods. Plasma levels of S100A8/A9 and interleukin‐1β were elevated in PR patients. Whole‐exome sequencing revealed novel polygenic mutations in HACL1 , KDM5A , RASAL1, HAVCR2 , PRDM9 , MBOAT4 , and JRKL . Conclusion In seronegative PR patients, we identified a distinct CD14+CD11b+CD36+ cell subset that can induce an inflammatory response under stress and exert antiinflammatory effects after phagocytosis of apoptotic cells, and a CD4+CD25–CD69+ T cell subset with pro‐ and antiinflammatory properties. Individuals with genetic mutations involving epigenetic modification, potentiation and resolution of stress‐induced inflammation/apoptosis, and a dysregulated endoplasmic reticulum stress response could be predisposed to seronegative PR.
Over-the-Counter Availability of Rescue Inhalers for Asthma
Authors: Sarah E. Gray, Valerie G. Press
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Purer Foods and Drugs
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal